L-citrulline protects against glycerol-induced acute renal failure in rats.

There is an increasing evidence that oxidative stress plays an important role in the pathogenesis of rhabdomyolysis-induced acute renal failure (ARF). In this study, protective effects of L-citrulline on glycerol-induced ARF in rats were investigated. Six groups of rats were employed in this study: group 1 served as a control; group 2 was only given glycerol (50%, 10 mL/kg, i.m.); group 3 was given glycerol plus dexamethasone (0.1 mg/kg, i.g.) as positive reference drug, starting at the same time as the glycerol injections; the last three groups were given glycerol plus L-citrulline (300, 600, and 900 mg/kg, i.g.) respectively, starting at the same time as the glycerol injections. The injections of glycerol were only once, and after glycerol injections the i.g. administrations of dexamethasone and L-citrulline were repeated every 24 h for 7 days. After 7 days of glycerol injections, the blood samples and kidney tissues were harvested for future biochemical and pathology analyses. The levels of creatinine (Cr) and urea nitrogen (BUN) in plasma, the content of malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO), the activity of total nitric oxide synthase (TNOS), inducible nitric oxide synthase (iNOS), endothelial NO synthase (eNOS), and superoxide dismutase (SOD) were evaluated in kidney tissues. Consequently, administrations of L-citrulline improved an impaired intrarenal oxygenation and kidney function compared with the glycerol group, and prevented the renal oxidative stress damage as well as severe functional and morphological renal deterioration. Therefore, L-citrulline might have potential application in the amelioration of glycerol-induced ARF.

Protective effect of rutin against acute gastric mucosal lesions induced by ischemia-reperfusion.

CONTEXT: Rutin, a flavonoid commonly present in onions, apples and tea, has been suggested to have a variety of pharmacological activities, including immunomodulator, anti-inflammatory and antioxidant activities. OBJECTIVES: The present study was to examine the protective effects of rutin on gastric mucosal damage induced by gastric ischemia-reperfusion (I/R) in rats. MATERIALS AND METHODS: Rutin (50, 100, 200 mg/kg) was administered intragastrically for five consecutive days before ischemia. Sixty minutes after the last administration of rutin, under anesthesia, the celiac artery was clamped for 30 min, and then the clamp was removed for 60 min reperfusion. After reperfusion, the stomach was removed for biochemical and histological examinations. RESULTS: As compared with the I/R group (116.7 ± 21.5), administration of rutin at doses of 50, 100 and 200 mg/kg significantly prevented the increase of gastric mucosal injury index induced by gastric I/R (73.4 ± 14.8, 65.9 ± 9.6 and 26.9 ± 5.7, respectively). ED50 value was 138.7 mg/kg. Moreover, rutin at doses of 50, 100 and 200 mg/kg showed an inhibition on the increased myeloperoxidase (24.6, 41.3 and 53.1% reduction) activity and malondialdehyde levels (27.4, 40.3 and 50.7% reduction) in gastric mucosa. Also, the elevation of inducible NO synthase (iNOS) activity as well as the decrease of constitutive NO synthase (cNOS) in the gastric mucosa were significantly prevented by rutin pretreatment. CONCLUSION: These results suggested that rutin has a protective effect against gastric mucosal injury induced by gastric I/R and that the gastroprotection was related to the NOS/NO pathway and its antioxidant activity.

High expression of brain-derived neurotrophic factor in intrahepatic cholangiocarcinoma is associated with intraneural invasion and unfavorable prognosis.

AIM: Brain-derived neurotrophic factor (BDNF) could promote the survival and differentiation of neural cells in peripheral and central nervous systems during development. Emerging evidences identified BDNF as an oncoprotein which could promotes progression and prognosis of tumors such as giloma, lung cancer and gastric cancer. We performed experiments to investigate the expression and clinical significance of BDNF in intrahepatic cholangiocarcinoma (IHCC). MATERIALS AND METHODS: The expression of BDNF and vascular endothelial growth factor (VEGF) was detected with immunohistochemistry in 96 patients with cholangiocarcinoma. The correlations between BDNF and the clinicopathologic factors were evaluated with Fisher test. The prognostic values of BDNF and VEGF were analyzed by the univariate analysis with Kaplan-Meier test and independent prognostic factor was identified by multivariate analysis with Cox-regression model. The effect of endogenous and exogenous BDNF on the invasion of IHCC cell line RBE was explored by transwell assay. RESULTS: The percentage of high expression of BDNF was 35.96% (34/96). High expression of BDNF was significantly associated with positive intraneural invasion (P=0.012) and low overall survival rate (P=0.006). High expression of BDNF was identified as an independent prognostic factor in IHCC (P=0.032). With Matrigel transwell assay, we demonstrated that both endogenous and exogenous BDNF could promote the invasion of IHCC cells. CONCLUSIONS: High expression BDNF was identified as an independent risk in IHCC indicating poorer prognosis. Both endogenous and exogenous BDNF could promote the invasion of IHCC cells, indicating that BNDF may promote IHCC invasion in a paracrine or autocrine pathway.

Orientin improves depression-like behavior and BDNF in chronic stressed mice.

SCOPE: Oxidative stress is involved in chronic stress-induced depression and the disruption of neurotransmission and neuroplasticity. Recently, orientin, a phenolic compound abundant in some fruits, millet, and herbs, has been shown to have antioxidant properties. This study investigated the potential antidepressant effects of orientin against chronic stress and its underlying mechanisms. METHODS AND RESULTS: The chronic unpredictable mild stress (CUMS) model was used to investigate the effects of orientin on behavior and biochemical alterations in mice. After 2 weeks of the CUMS protocol, the mice were treated with orientin (20 mg/kg and 40 mg/kg, oral gavage) for 3 weeks. Administration of orientin significantly alleviated the CUMS-induced depression-like behavior, including sucrose preference reduction, locomotor activity decline, and hypomotility. Orientin treatment attenuated the oxidative stress markers and increased the concentrations of serotonin and norepinephrine in the hippocampus and prefrontal cortex of CUMS mice. Orientin treatment also increased the brain-derived neurotrophic factor and synapse-associated proteins (synaptophysin and postsynaptic density protein 95) of CUMS mice. CONCLUSION: Orientin exerts antidepressant-like effects on CUMS mice, specifically by improving central oxidative stress, neurotransmission, and neuroplasticity. Therefore, supplementation with orientin-enriched food or fruit could be beneficial as a preventive strategy for chronic stress-induced depression.

Luteolin protects against high fat diet-induced cognitive deficits in obesity mice.

The epidemic and experimental studies have confirmed that the obesity can lead to neuroinflammation, neurodegenerative diseases and adversely affect cognition. Despite the numerous elucidations on the impact of obesity on cognition decline, the contributors to the impairments in obesity remain unclear. Male C57BL/6J mice were fed either a control or high-fat diet (HFD) for 16 weeks and then randomized into four groups treated with their respective diets for 4 weeks including control diet (CD); control diet+luteolin (CDL); high-fat diet (HFD), high-fat diet+luteolin (HFDL). The dose of luteolin was 10mg/kg, oral. We showed that adding luteolin in high-fat diet can significantly reduce body weight gain, food intake and plasma cytokines as well as improving glucose metabolism of mice on HFD. Importantly, we showed that luteolin treatment had the effects of alleviating neuroinflammation, oxidative stress and neuronal insulin resistance in the mouse brain, restored blood adipocytokines level to normal. Furthermore, luteolin increased the level of brain-derived neurotrophic factor (BDNF), the action of synapsin I (SYP) and postsynaptic density protein 95 (PSD-95) in the cortex and hippocampus as to that the behavioral performance in Morris water maze (MWM) and step-through task were significantly improved. These results indicate a previously unrecognized potential of luteolin in alleviating obesity-induced cognitive impairment for type-2 diabetes mellitus and Alzheimer disease (AD).

Antidepressant-like effects of tea polyphenols on mouse model of chronic unpredictable mild stress.

Tea polyphenols (TPs), which are the natural compounds extracted from tea leaves, possess a number of beneficial properties, such as reducing the risks of cancer and heart diseases, alleviating cognitive impairments and showing antidepressant-like activity in the forced swim test (FST) and tail suspension test (TST). The present study was designed to investigate the protective effect of TPs on the chronic unpredictable mild stress (CUMS)-induced depression model in mice and to elucidate the related underlying mechanisms. With the daily exposure to stressor for 5 consecutive weeks, TPs were administered in mice at a daily dose of 25 mg/kg or 50 mg/kg by gavage for 3 consecutive weeks from the 3rd week. Our results showed that CUMS significantly decreased the levels of serum serotonin (5-HT) and norepinephrine (NE) in the hippocampus, the prefrontal cortex and serum, and the activities of superoxide dismutase (SOD) and catalase (CAT), with an increase in lipid peroxidation level as well as a reduction in glutathione (GSH) level and an elevation in the production of malondialdehyde (MDA) in the hippocampus and the prefrontal cortex. CUMS also reduced open-field activity, sucrose consumption, as well as increased immobility duration in FST and TST. TPs administration could effectively reverse the alterations in the concentrations of 5-HT and NE, elevate the activities of SOD and CAT as well as the level of GSH, reduce the MDA level and inhibit lipid peroxidation. Moreover, TPs could effectively reverse alterations in immobility duration, sucrose consumption and open-field activity. In conclusion, TPs administration has exhibited significant antidepressant-like effects in mice with CUMS-induced depression. The antidepressant activity of TPs might be related to the alteration of monoaminergic responses and antioxidant defenses.

Protective effects of luteolin on cognitive impairments induced by psychological stress in mice.

In the present study, the protective effects of luteolin were investigated against psychological stress-induced cognitive impairment. To emulate the psychological stress, mice received restraint stress for six hours daily, between 9:00 and 15:00 hours, for 21 consecutive days. The results of step-through test, open-field test and Morris Water Maze test demonstrated that psychological stress treatment could result in cognitive impairments in mice. This cognition dysfunction was improved by treatment with low- and medium-dose luteolin. In addition, psychological stress induced an increased serum corticosterone concentration with a decreased serum norepinephrine and dopamine concentration. These alterations were attenuated by treatment with luteolin. Also, psychological stress significantly decreased the glutathione (GSH) concentrations and superoxide dismutase (SOD) activities in prefrontal cortex and hippocampus, while the malondialdehyde (MDA) concentrations were enhanced. However, these oxidative alterations in prefrontal cortex and hippocampus induced by psychological stress were significantly reversed by treatment of luteolin. Further, the current study indicated a decline of catalase (CAT) activities in the hippocampus of the ST group, which was significantly prevented by low, medium and high dose of luteolin. On the other hand, there was no significance in CAT activities of the prefrontal cortex among the six groups. Collectively, the present results suggest that luteolin treatment serves as a key role in improving the psychological stress-induced cognitive impairments.

Protective effect of l-citrulline against ethanol-induced gastric ulcer in rats.

We examined the protective effect of l-citrulline on ethanol-induced gastric ulcer in rats. Administration of l-citrulline at doses of 300, 600 and 900mg/kg body weight prior to ethanol ingestion protected the stomach from ulceration. The gastric lesions were significantly attenuated by all doses of l-citrulline as compared to the ethanol group. Pre-treatment with l-citrulline prevented the oxidative damage and the decrease of nitric oxide content as well as the increase of the myeloperoxidase activity. Consequently, significant changes observed included the attenuation in the elevation in total nitric oxide synthase activity and inducible nitric oxide synthase activity as well as the decrease in constitutive nitric oxide synthase activity in the gastric mucosa induced by ethanol. Analysis of serum cytokines of ethanol-induced rats showed a moderate decrease in interleukin-10 with considerable increase of interleukin-6 while l-citrulline inhibited the acute alteration of cytokines. These results suggested the gastroprotective effect of l-citrulline.